Psychostimulant abuse is a significant public health problem, with 2.1 million Americans reporting cocaine use and 1.9 million reporting methamphetamine use. Currently, there are no FDA-approved pharmacotherapies to treat stimulant dependence. Previous cocaine medications development efforts have focused on small molecule drugs as they can readily enter the brain. The lack of brain penetrance by large molecules was seen as a critical barrier to the use of neuropeptides for cocaine addiction and other central nervous system (CNS) disorders. This is unfortunate as a large body of animal studies support the potential of neuropeptides to treat substance-use disorders. The physiology of the blood-brain barrier (BBB) presents an attractive solution to this dilemma, as although under normal conditions most neuropeptides do not enter the brain because their sizeprevents passive, the BBB endothelium is equipped with a variety of molecular active transport systems that use processes such as receptor-mediated transcytosis to transport macromolecules like insulin and transferrin between blood and brain. We have validated a procedure to conjugate biocompatible, biodegradable, and FDA-approved nanoparticles to state-of-the-art brain targeting ligands. These brain-targeting ligands then allow the nanoparticles to undergo receptor-mediated transcytosis into the brain, and then release the neuropeptide over a sustained timecourse to act at their central receptors. In the proposed studies, we will focus on enhancement of the brain penetrance of the hormone oxytocin because of the substantial body of previous studies showing that oxytocin attenuates the abuse-related effects of psychostimulants. Although we will focus on the development of this technology using oxytocin, we believe that this new technology will be applicable to many other neuropeptides (such as neuropeptide Y) that have shown promise for substance-use disorders. Demonstrating the feasibility of our approach, we have collected compelling preliminary data showing our nanoparticles do not exhibit in vitro or in vivo toxicity, can be optimized to achieve sizes on the order of 100nm (which is highly amenable to brain delivery), increase the brain penetrance of an IR-marker (of similar molecular size to oxytocin) using bioimaging, engender stronger prosocial effects than oxytocin solution given intranasally, suppress the behavioral effects of cocaine, and exhibit sustained release effects both in vitro and in vivo. We propose to engage in reproducibility assessments to further characterize the CNS bioavailability (using cell culture and bioimaging), to further establish the therapeutic efficacy in an animal model of cocaine-use disorder, and to determine the benefits of nasal- vs. IP and IV administration of this formulation.